Cancer is the leading cause of death after heart disease in the U.S. Although progress has been made in the diagnosis and treatment of various cancers, these diseases still result in significant morbidity. Esophageal and gastric cancers are among the most highly lethal types of cancer worldwide, with an annual incidence of approximately 1.5 million cases. The five-year relative survival rate for gastric cancer cases diagnosed in the United States has improved only from 16% to 24% over the last 30 years (Jemal, A. et al. Cancer statistics, 2007. CA Cancer J Clin. 2007:57, 43-46), highlighting the need for more effective therapies. In addition, in Western countries, there has been a steady rise in adenocarcinomas of the gastric cardia and gastroesophageal junction, which has been associated with increased body mass index (Merry, A., et al. Gut. 2007:56, 1503-1511). Gene amplification is one of the most frequent genetic alterations in gastric cancer and is believed to play a major role in its development and progression.
Lung cancer is a heterogeneous group of disorders that is subdivided into molecular subtypes with dedicated targeted therapies. Non-small cell lung cancer (NSCLC) is a common cancer with high mortality and few effective treatment options. NSCLC includes diverse types of diseases such as adenocarcinoma, squamous cell carcinoma, undifferentiated large cell carcinoma, adenosquamous carcinoma (pleiomorphic carcinoma), sarcomatoid carcinoma and others.
MET encodes a transmembrane tyrosine kinase receptor for Hepatocyte Growth Factor (HGFR), which is implicated in various oncogenic processes including cell proliferation, survival, invasion, motility and metastasis. MET can be activated either by binding to its ligand HGF, high Met expression/amplification, mutation, or decreased degradation. These mechanisms for MET activation are now being therapeutically targeted in vitro, in tumor xenograft models, in vivo and in clinical trials. High expression and amplification are different phenomena and present different diagnostic targets and/or treatment opportunities. High expression or over expression can result from a single unamplified gene, and an amplified gene does not always lead to greater expression levels of mRNA and protein. Thus, it is not possible to predict whether one phenomenon will lead to another, or whether they are related. However, amplification and high expression can be indicative of certain cancers and precancers. In particular, recent findings underscore the prognostic and potentially predictive value of MET amplification as well as challenges in identifying patient subgroups that may benefit from targeted cancer therapies (Lennerz, J. K. et al., J. Clin. Oncol. 29, 2011, p. 1-8). Currently there are no validated biomarkers to evaluate increased MET copy number, which leads to confusion in the literature about MET amplification and polysomy (Peters, S. et al., Nat. Rev. Clin. Oncol. 9, 314-326 (2012)). Thus, there is a need to identify and treat patients who will most benefit from particular therapies and to provide the most tailored and appropriate therapy to each individual person in need.